Type 2 diabetes (T2DM) constitutes an enormous health burden in the United States, and despite increasing prevalence there are still major gaps in understanding the pathogenesis of this disease. The overall goal of this proposal is to determine the role of the regulatory peptide glucagon-like peptide 1 (GLP-1) to regulate glucose tolerance in nondiabetic persons and patients with T2DM. GLP-1 regulates islet hormone secretion and is essential for normal glucose tolerance. Importantly, GLP-1 is effective at lowering blood glucose in persons with T2DM, and two new classes of antidiabetes drugs are based on GLP-1 signaling. Despite the promise surrounding the clinical application of GLP-1 major questions remain about its mechanism of action. A better understanding of the endogenous GLP-1 system is critical for its optimal utilization to treat diabetes. It has generally been accepted that GLP-1 acts by an endocrine mechanism and that the intestine is the sole source of this peptide in the circulation. However, there is emerging evidence to question the importance of circulating peptide as the primary mediator of GLP-1 actions. Moreover, since the GLP-1 receptor is expressed in discrete regions of the brain and peripheral nervous system by neurons involved in metabolism, neural mediation of GLP-1 is a plausible alternative to an endocrine mechanism of action. We have data from recent experiments that implicate central and peripheral nervous signaling as contributing to GLP-1 mediated glucose tolerance. In this application we propose to determine the importance of neural mechanisms in mediation GLP-1 effects. The specific aims of this project will determine: 1) the relative contributions of 2-cell and neural GLP-1 receptors to glucose tolerance; 2) whether GLP-1 produced in the brain regulates insulin secretion and the control of glucose after meals; 3) the role of circulating GLP-1 to mediate the gluco-regulatory effects of GLP-1 in healthy and diabetic humans. Investigating the role of neural GLP-1 signaling on insulin secretion and whole body glucose homeostasis will advance knowledge of metabolic regulation with the potential to expand the clinical role of the GLP-1 system for treating diabetes. PUBLIC HEALTH RELEVANCE: GLP-1 is a GI hormone that has a broad range of effects to promote glucose disposal. Several new drugs have been developed that improve blood glucose control in diabetic patients by acting through the GLP-1 system. The goal of this project is to understand the different mechanisms by which GLP-1 acts to allow new and more refined applications of this system to the treatment of diabetes.